NEURAL MECHANISMS OF CORTISOL SUPPRESSION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。确定社会地位较低的雌性狨猴的社会心理诱导的皮质醇抑制是否部分由脑或垂体水平的内分泌抑制介导，作为理解与各种人类神经精神疾病相关的慢性内分泌失调的模型。低皮质醇症，或肾上腺皮质分泌皮质醇不足，可能发生在人类早期或创伤性应激的结果，并可能在许多应激相关疾病的病理生理学中发挥重要作用；然而，很少有动物模型可用于研究潜在的机制。雌性普通狨猴提供了一种有希望的应激相关皮质醇降低的灵长类模型，因为它们在社会群体中成为从属地位后，循环皮质醇会长期减少。在这项研究中，我们用皮质醇合成抑制剂metyrapone和促肾上腺皮质激素释放因子（CRF）治疗主导和从属雌性，以表征从属对下丘脑-垂体-肾上腺轴中枢调节的影响。7只优势雌性和6只从属雌性小鼠接受CRF治疗，然后用甲替拉酮或水预处理。测定血浆促肾上腺皮质激素（ACTH）和皮质醇浓度，在美替拉酮或水治疗前，以及随后的CRF治疗后。在美替拉酮治疗后，下属的皮质醇水平与上级相似，但ACTH水平明显升高。在CRF挑战期间，下属的皮质醇浓度较低，ACTH浓度较高，尽管对CRF的净综合反应没有差异。下属的皮质醇- acth比率一直较低。这些结果证实了先前发现的低皮质醇浓度和下属肾上腺反应迟钝，并表明当皮质醇水平差异消除时，下属表现出夸大的下丘脑对垂体的驱动。这些次要狨猴的神经内分泌改变类似于创伤后应激障碍患者和儿童虐待的成年幸存者。本研究使用WNPRC动物服务（狨猴群）和化验服务。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To determine whether psychosocially induced suppression of cortisol in socially subordinate female marmosets is mediated, in part, by endocrine inhibition at the level of the brain or pituitary, as a model for understanding chronic endocrine dysregulation associated with a variety of human neuropsychiatric disorders. Hypocortisolism, or insufficient secretion of cortisol from the adrenal cortex, may occur in humans as a consequence of early or traumatic stress and may play a fole in the pathophysiology of numerous stress-related disorders; however, few animal models are available for investigation of the underlying mechanisms. Female common marmosets offer a promising primate model of stress-related hypocortisolism, as they undergo chronic reductions in circulating cortisol after becoming subordinate in a social group. In this study, we treated dominant and subordinate females with the cortisol synthesis inhibitor metyrapone and corticotropin-releasing factor (CRF), to characterize the effects of subordination on central regulation of the hypothalamic-pituitary-adrenal axis. Seven dominant and six subordinate females were treated with CRF, following pretreatment with metyrapone or water. Plasma adrenocorticotropin (ACTH) and cortisol concentrations were determined before metyrapone or water treatment, and, subsequently, after CRF treatment. Following metyrapone treatment, subordinates had similar cortisol levels to dominants, but significantly higher ACTH levels. During CRF challenges, cortisol concentrations were lower and ACTH concentrations higher in subordinates, although net integrated responses to CRF did not differ. Cortisol-to-ACTH ratios were consistently lower in subordinates. These results confirm previous findings of low cortisol concentrations and blunted adrenal responsiveness in subordinates, and suggest that when differences in cortisol levels are eliminated, subordinates exhibit exaggerated hypothalamic drive to the pituitary. These neuroendocrine alterations in subordinate marmosets resemble those in posttraumatic stress disorder patients and adult survivors of child abuse. This research used WNPRC Animal Services (marmoset colony) and Assay Services.